Journal
NATURE CELL BIOLOGY
Volume 13, Issue 4, Pages 475-U291Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2223
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Funding
- NIH [GM65933]
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Accurate chromosome segregation depends on biorientation, whereby sister chromatids attach to microtubules from opposite spindle poles. The spindle-assembly checkpoint is a surveillance mechanism in eukaryotes that inhibits anaphase until all chromosomes have bioriented(1-3). In present models, the recruitment of the spindle-assembly checkpoint protein Mad2, through Mad1, to non-bioriented kinetochores is needed to stop cell-cycle progression(3-6). However, it is unknown whether Mad1-Mad2 targeting to kinetochores is sufficient to block anaphase. Furthermore, it is unclear whether regulators of biorientation (for example, Aurorakinases(7)) have checkpoint functions downstream of Mad1-Mad2 recruitment or whether they act upstream to quench the primary error signal(8). Here, we engineered a Mad1 construct that localizes to bioriented kinetochores. We show that the kinetochore localization of Mad1 is sufficient for a metaphase arrest that depends on Mad1-Mad2 binding. By uncoupling the checkpoint from its primary error signal, we show that Aurora, Mps1 and BubR1 kinases, but not Polo-like kinase, are needed to maintain checkpoint arrest when Mad1 is present on kinetochores. Together, our data suggest a model in which the biorientation errors, which recruit Mad1-Mad2 to kinetochores, may be signalled not only through Mad2 template dynamics(9), but also through the activity of widely conserved kinases, to ensure the fidelity of cell division.
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